SK122000A3 - Pharmaceutical compositions comprising an aldose reductase inhibitor and an ace inhibitor - Google Patents

Abstract

The invention relates to pharmaceutical compositions comprising an aldose reductase inhibitor and an ACE inhibitor, and their use in the treatment of diabetic complications such as diabetic neuropathy, diabetic retinopathy and diabetic nephropathy.

Description

Technical field

The invention relates to pharmaceutical compositions, and in particular to pharmaceutical compositions comprising an aldose reductase inhibitor (ARI) and an angiotensin converting enzyme (ACE) inhibitor, which are useful in preventing and treating complications of diabetes mellitus.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a chronic disease characterized by hyperglycemia and complications including diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cataracts and the like. Although various investigators have studied the use of ACE inhibitors or aldose reductase inhibitors independently of each other in similar conditions, no one has proposed the combination therapy of the present invention.

Prolonged administration of an ACE inhibitor at a therapeutically effective dose may be harmful or may increase side effects in some patients, for example, leading to a significant deterioration of kidney function, induction of hyperkalaemia, neurotropinia, angioneurotic edema, rash or diarrhea, or worsening of dry cough. Administration of ARI may also increase the deleterious effects or side effects at doses required to inhibit the enzyme aldose reductase and sufficient to produce a significantly beneficial therapeutic effect. The present invention alleviates the problems associated with administering an ARI or an ACE inhibitor alone, and / or provides a means to achieve a therapeutic effect that is significantly greater than that achieved with the individual agents when administered alone. Diabetic complications further include a complex of mechanisms or multiple mechanisms that cause a cascade of biochemical changes and which in turn lead to structural changes. This can result in different patient groups. A further advantage of the present invention is that it allows treatment to be adapted to the needs of individual patient groups.

SUMMARY OF THE INVENTION

The invention relates to a pharmaceutical composition comprising an aldose reductase inhibitor and an ACE inhibitor together with a pharmaceutically acceptable carrier and / or diluent.

Suitable aldose reductase inhibitors useful in the compositions of the invention include, for example, epalrestat, tolrestat, ponrestat, zopolrestat, AD-5467, SNK-860, ADN-138, AS-3201, zenarestat, sorbinil, metosorbinil, imirestat, minalrestat (WAY-121) 509) and ZD 5522 (3 ¹ , 5 ¹ -dimethyl-4'-nitromethylsulfonyl-2- (2-tolyl) acetanilide, the preparation of which is described in European Patent Application No. 469887, Examples 3 and 60), or a pharmaceutically acceptable salt thereof. A preferred aldose reductase inhibitor is, for example, ZD 5522.

Suitable ACE inhibitors useful in the compositions of this invention include, for example, benazepril, benazeprilat, captopril, delapril, fentiapril, fosinopril, libenzapril, moexipril, pentopril, perindopril, pivopril, quinapril, quinaprilat, ramipril, spirapril, zeropril, spofenpri, spofenpri , indolapril, lisinopril, alacepril and cilazapril, or a pharmaceutically acceptable salt thereof. A preferred ACE inhibitor is, for example, lisinopril.

Independent embodiments of the present invention pertain to a pharmaceutical composition comprising any of the aforementioned aldose reductase inhibitors and the aforementioned ACE inhibitors, together with a pharmaceutically acceptable carrier and / or diluent. Other independent embodiments of the present invention include the following:

(1) a pharmaceutical composition comprising epalrestate and lisinopril, together with a pharmaceutically acceptable carrier and / or diluent;

(2) a pharmaceutical composition comprising tolrestat and lisinopril, together with a pharmaceutically acceptable carrier and / or diluent;

(3) a pharmaceutical composition comprising ponolrestat and lisinopril, together with a pharmaceutically acceptable carrier and / or diluent;

(4) a pharmaceutical composition comprising zopolrestat and lisinopril, together with a pharmaceutically acceptable carrier and / or diluent;

(5) a pharmaceutical composition comprising AD-5467 and lisinopril, together with a pharmaceutically acceptable carrier and / or diluent;

(6) a pharmaceutical composition comprising SNK-860 and lisinopril, together with a pharmaceutically acceptable carrier and / or diluent;

(7) a pharmaceutical composition comprising ADN-138 and lisinopril, together with a pharmaceutically acceptable carrier and / or diluent;

(8) a pharmaceutical composition comprising AS-3201 and lisinopril, together with a pharmaceutically acceptable carrier and / or diluent;

(9) a pharmaceutical composition comprising zenarestat lisinopril, together with a pharmaceutically acceptable carrier and / or diluent;

(10) a pharmaceutical composition comprising sorbinil and lisinopril, together with a pharmaceutically acceptable carrier and / or diluent;

(11) a pharmaceutical composition comprising methosorbinil and lisinopril, together with a pharmaceutically acceptable carrier and / or diluent;

(12) a pharmaceutical composition comprising imirestat and lisinopril, together with a pharmaceutically acceptable carrier and / or diluent;

(13) a pharmaceutical composition comprising minalrestat and lisinopril, together with a pharmaceutically acceptable carrier and / or diluent.

A preferred pharmaceutical composition of the invention comprises an ZD 5522 aldose reductase inhibitor or a pharmaceutically acceptable salt thereof and an ACE inhibitor (including any of the aforementioned ACE inhibitors), together with a pharmaceutically acceptable carrier and / or diluent.

A particularly preferred pharmaceutical composition of the invention comprises the ZD 5522 aldose reductase inhibitor or a pharmaceutically acceptable salt thereof and the ACE inhibitor lisinopril or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent and / or carrier.

The pharmaceutically acceptable salts of the aldose reductase inhibitors and ACE inhibitors of the invention are salts with physiologically acceptable bases and / or acids, which are well known to those skilled in the art of pharmaceutical technology. Suitable salts with physiologically acceptable bases are, for example, alkali metal salts such as sodium, potassium, calcium or magnesium salts; and ammonium salts and salts with suitable organic bases such as methylamine, dimethylamin, trimethylamine, piperidine, morpholine and triethanolamine. Suitable salts with physiologically acceptable acids are, for example, salts with inorganic acids such as hydrohalides (especially hydrochlorides or hydrobromides), sulfates and phosphates and salts with organic acids.

The pharmaceutical compositions of this invention may be administered in a conventional manner, for example by oral or parenteral administration, using conventional systemic dosage forms such as tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions, sterile injectable aqueous or oily solutions, or suspension. These dosage forms may contain the necessary carriers, excipients, glidants, buffers, extenders, antioxidants, dispersants and the like.

In particular, compositions for oral administration are preferred.

The dosages of the aldose reductase inhibitor and the ACE inhibitor that can be administered according to the invention depend on various factors, such as age, weight and severity of the condition being treated, as well as the mode of administration, dosage form and dosing method and regimen, the desired result and additionally the activity of a particular aldose reductase inhibitor and an ACE inhibitor used in the composition. In addition, the recommended highest dose of ACE inhibitors should be taken into account.

The dosage unit of the preparation, such as a tablet or capsule, can usually contain, for example, from 0.1 mg to 500 mg of the aldose reductase inhibitor and from 0.1 mg to 500 mg of the ACE inhibitor. Preferably, the dosage unit of the formulation may contain from 0.1 mg to 100 mg of the aldose reductase inhibitor and from 0.1 mg to 100 mg of the ACE inhibitor.

The pharmaceutical compositions of the invention may be administered up to six times a day, usually 1 to 4 times a day, and preferably 1 to 2 times a day, so that not only is the daily dose of the aldose reductase inhibitor usually administered from 0.01 to 100 mg / kg, preferably 0.1 up to 10 mg / kg, more preferably from 0.1 to 5 mg / kg, but also a dose of an ACE inhibitor in the usual range from 0.01 to 100 mg / kg, preferably from 0.01 to 20 mg / kg, more preferably from 0, 01 to 1 mg / kg.

The invention protects a combination (or product containing) an aldose reductase inhibitor and an ACE inhibitor, for simultaneous, separate or sequential use in the treatment of diabetic complications. In one embodiment of the present invention, the aldose reductase inhibitor or a pharmaceutically acceptable salt thereof and the ACE inhibitor or a pharmaceutically acceptable salt thereof are formulated as a mixture in a single pharmaceutical dosage form. In another case, the present invention protects the separate administration of individual dosage units of an aldose reductase inhibitor and an ACE inhibitor to achieve the desired therapeutic effect. Such individual dosage units may be administered simultaneously or sequentially as determined by the physician. Preferably both the aldose reductase inhibitor and the ACE inhibitor are administered orally. Accordingly, the present invention provides a composition for treating diabetic complications comprising a pharmaceutically acceptable carrier and / or diluent and, as active ingredients, an aldose reductase inhibitor and an ACE inhibitor in amounts that produce a synergistic therapeutic effect.

In another aspect, the invention relates to a combination of pharmaceutical compositions for the combined therapy of diabetic complications, the combination comprising a pharmaceutical composition comprising an aldose reductase inhibitor and a pharmaceutical composition comprising an ACE inhibitor. Significant diabetic complications include, for example, diabetic neuropathy, diabetic nephropathy, and diabetic retinopathy.

Another aspect of the present invention is the use of an aldose reductase inhibitor and an ACE inhibitor for the preparation of pharmaceutical compositions for use in the treatment of diabetic complications.

The invention further provides a method of treating diabetic complications (such as diabetic neuropathy, diabetic nephropathy or diabetic retinopathy) by administering a systemically therapeutically effective amount of an aldose reductase inhibitor together with an ACE inhibitor, for example, orally or parenterally. When the patient to be treated is normotensive, the ACE inhibitor should be administered in amounts lower than those required to lower blood pressure. When the patient to be treated is hypertensive, the ACE inhibitor should be used earlier in the amounts usually used to treat hypertension. The present invention provides a new method of treating diabetic complications and the amounts of the aldose reductase inhibitor and the ACE inhibitor that are required when administered in combination therapy are lower than usual, and thus adverse effects or side effects are minimized.

The effect of the pharmaceutical composition of the invention can be investigated using one or more published models of diabetic complications well known in the art. The pharmaceutical compositions of the present invention are particularly useful for preventing, reducing the development or altering the deficiencies of nerve function found in diabetic patients, and hence particularly useful for treating diabetic neuropathy. This can be demonstrated, for example, by measuring markers such as nerve conduction velocity, nerve amplitude, quantitative sensory evaluation, testing for autonomous function and morphometric change. Experimental studies analogous to those described may be carried out (Diabetology, 1992, vol. 35, pp. 12-18 and 1994, vol. 37, pp. 651-663).

methods of treatment or associated with a reduced warm-blooded animal

Further, the present invention relates to the prevention of disease states at the rate of neuronal conduction in (including human) in need of such treatment; the method comprising administering to said animal a therapeutically effective amount of a combination of an aldose reductase inhibitor and an ACE inhibitor. Another possibility of this invention is the use of an aldose reductase inhibitor and an ACE inhibitor for the manufacture of a medicament for use in the treatment or prevention of disease states associated with reduced neuronal conduction velocity.

It is a further object of the present invention to provide a method of reversing the decreased rate of nuronal conduction in a warm-blooded animal (including a human) in need of such treatment; the method comprising administering to said animal a therapeutically effective amount of a combination of an aldose reductase inhibitor and an ACE inhibitor. Yet another object of the present invention is the use of an aldose reductase inhibitor and an ACE inhibitor for the manufacture of a medicament for use in reversing a reduced rate of neuronal conduction.

The following examples illustrate the invention but do not limit it in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Suitable pharmaceutical compositions of an aldose reductase inhibitor (ARI) such as ZD 5522 include the following components:

Tablet 1 mg / tablet

ARI 100

Lactose Pharm.Eur. 182,75

Croscarmellose sodium 12.0

Corn starch paste 2.25 (5% w / v)

Magnesium stearate 3.0

Tablet 2

ARI 50

Lactose Pharm.Eur. 223.75

Croscarmellose sodium 6.0

Corn starch 15,0

Polyvinylpyrrolidone 2.25 (5% w / v paste)

Magnesium stearate 3.0

Tablet 3

ARI 1,0

Lactose Pharm.Eur. 93.25

Croscarmellose sodium 4.0

Corn starch 0,75 (paste 5% w / v)

Magnesium stearate 1.0

Capsule 1

ARI

Lactose Pharm.Eur. Magnesium stearate

10.0

488.5

1.5

Example 2

Suitable pharmaceutical ACE inhibitor compositions comprise the following components:

Tablet 1

ACE 100 inhibitor

Wheat starch

Gelatin 7,5

Microcrystalline cellulose 25

Magnesium stearate 2,5

Tablet 2

ACE inhibitor 20 Preserved starch 82 Microcrystalline cellulose 82 Magnesium stearate 1

Example 3

Suitable pharmaceutical compositions comprising an ARI and an ACE inhibitor in the form of a dosage unit consist of the following components:

tablet

ARI

Inhibitor ACE

Wheat starch

gelatin

Microcrystalline cellulose Magnesium stearate

Example 4

A patient in need of treatment for diabetic neuropathy receives ZD 5522 (70 mg) and lisinopril (10 mg). Each compound is administered twice daily.

Example 5

Male Sprague-Dawley rats, 19 weeks of age at the start of the study, were divided into groups of animals without diabetes (normal control group) and animals with diabetes induced by intraperitoneal administration of streptozotocin (40-45 mg / kg, freshly dissolved in sterile saline). Diabetes was verified after 24 hours by determining hyperglycemia and glucose (Visidex II and Distix; Ames, Slough, UK). Diabetic rats were tested for weeks and weighed daily. Animals were discarded when plasma glucose concentration was less than 20 mM or when body weight increased substantially over 3 days. Samples were taken from the tail vein or carotid artery after recent plasma glucose determination experiments (GOD-Perid method; Boehringer Mannheim, Mannheim, Germany). After 6 weeks of untreated diabetes, groups of rats were treated for an additional 2 weeks with lisinopril (0.3 mg / kg / day) or an aldose reductase inhibitor ZD 5522 (0.25 mg / kg / day) or a combination of the two drugs dissolved in drinking water. At the end of the treatment period, rats were anesthetized with thiobutabarbitone, administered by intraperitoneal injection (50-100 mg / kg).

Trachea was cannulated for artificial ventilation and a carotid cannula was used to monitor mean systemic blood pressure. Motor motor conduction velocity was measured (as described previously by Cameron et al., Diabetology, 1993, vol. 36, pp. 299-304) between sciatic notch and nodal branch to anterior tibial muscle, which is representative of the entire sciatic nerve in conditions of accessibility to diabetes and the effect of treatment.

The results

Nerve conduction velocity (mean ± SEM) is 64.4 ± 0.5 m / s in non-diabetic control rats and decreased to 50.9 ± 0.5 m / s in untreated diabetes (p < 0.001). Treatment with lisinopril or ZD 5522 induced a small (-20%) but statistically significant increase in conduction velocity to 53.9 ± 0.6 (p less than 0.01) to 53.7 ± 0.3 (p less than 0.001). m / s. In the combination treatment, conduction velocity was in non-diabetic ranges of 63.85 ± 0.41 (p less than 0.001 versus the diabetic control group). This increase in conduction velocity was considerably greater than that assumed only from the sum of the effects of both drugs (56.1 m / s, p lower than 0.0001, t-test per sample).

Industrial usability

The invention provides improved possibilities for the prevention and treatment of diabetes and its associated complications by administering pharmaceutical compositions comprising both an aldose reductase inhibitor (ARI) and an angiotensin converting enzyme (ACE) inhibitor. These compositions are formulated in known dosage forms (tablets, capsules), which can be manufactured by technically unpretentious manufacturing procedures common in the pharmaceutical industry. The advantages of these measures are lower dosages and fewer side effects.

A pharmaceutical composition comprising an aldose reductase inhibitor and an angiotensin converting enzyme inhibitor, together with a pharmaceutically acceptable carrier and / or diluent.

Claims (10)

PATENT CLAIMS Pharmaceutical composition according to claim 1, characterized in that the aldose reductase inhibitor is selected from the group consisting of epalrestate, tolrestate, ponolrestat, zopolrestat, AD-5467, SNK-860, ADN-138, AS-3201, zenarestat, sorbinil, methosorbinil, imirestat, minalrestat and ZD 5522, or a pharmaceutically acceptable salt thereof. Pharmaceutical converting enzyme benazepril, fosinopril, composition according to claim 1 or 2, wherein the angiotensin inhibitor is selected from the group consisting of benazeprilat, captopril, delapril, fentiapril, libenzapril, moexipril, pentopril, perindopril, quinopril, quinopril, quinopril, quinopril, quinopril, quinopril , quinaprilat, ramipril, spirapril, spiraprilat, zofenopril, ceronapril, enalapril, indolapril, lisinopril, alacepril and cilazapril, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 1, 2 or 3, wherein the aldose reductase inhibitor is ZD 5522 or a pharmaceutically acceptable salt thereof. 5. A pharmaceutical characterized by a converting enzyme acceptable salt. composition according to claim 1, 2, 3 or 4, wherein the angiotensin inhibitor is lisinopril or a pharmaceutical A pharmaceutical composition according to any preceding claim for use in the treatment of diabetic complications. Use of an aldose reductase inhibitor and an angiotensin converting enzyme inhibitor for the preparation of a pharmaceutical composition for use in the treatment of diabetic complications. Use of an aldose reductase inhibitor and an angiotensin converting enzyme inhibitor for the manufacture of a medicament for treating or preventing the development of disease states associated with reduced neuronal conduction velocity. Use of an aldose reductase inhibitor and an angiotensin converting enzyme inhibitor for the manufacture of a medicament for use in reversing a reduced rate of neuronal conduction. Use of an aldose reductase inhibitor and an angiotensin converting enzyme inhibitor for the manufacture of a medicament for use in the treatment of diabetic neuropathy.